Intestinal epithelial cell exfoliation by caspases

Caspases 导致肠上皮细胞脱落

• 批准号: 10395547
• 负责人: Edward A Miao
• 金额: $ 44.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-03 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395547
• 关键词: Adherence; Adhesions; Animals; Apoptosis; Apoptotic; Back; Bacteria; Bacterial Infections; Bacterial Translocation; Body Surface Area; CASP1 gene; CASP3 gene; CASP7 gene; Cardiovascular system; Caspase; Cell Death; Cell Line; Cell membrane; Cells; Coculture Techniques; Cytosol; Data; Epithelial Cells; Event; Exposure to; Family; Flagellin; Focal Adhesions; Grant; Immune; Immune system; In Vitro; Infection; Inflammasome; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1 beta; Interleukin-18; Intestines; Invaded; Link; Lymphocyte; Lytic; Methods; Microbe; Mind; Mus; Needles; Nutrient; Oral; Organoids; Oxygen; Pathway interactions; Proteins; Rod; Role; Salmonella typhimurium; Signal Pathway; Signal Transduction; Surveys; System; Type III Secretion System Pathway; Virulence Factors; cell type; crosslink; extracellular; fighting; gastrointestinal infection; gut colonization; in vivo; intestinal epithelium; intraepithelial; lambda Spi-1; macrophage; member; novel; oral infection; pathogen; pathogenic bacteria; programs; sensor

ABSTRACT Many bacterial pathogens attempt to adhere to or invade intestinal epithelial cells (IECs), often using virulence factors that manipulate cytosolic signaling pathways in the IEC. However, IECs are able to survey their cytosol by using innate immune sensors in the inflammasome family. We have shown that inflammasomes can detect the activity of bacterial secretion systems by detecting aberrant translocation of bacterial flagellin, rod, and needle proteins. Inflammasomes have largely been studied in macrophages, where active caspase-1 was first shown to cleave pro-IL-1β and pro-IL-18 to their mature and released forms. Caspase-1 was recently shown to cleave a third protein, gasdermin D, which forms a pore in the plasma membrane that causes programmed lytic cell death, or pyroptosis. The function of caspase-1 in other cell types is now beginning to be studied, and these may be slightly different from its function in macrophages. In this regard, in IECs inflammasomes were recently shown to drive exfoliation of the compromised IEC, ejecting it into the gut lumen. Caspase-1 is the founding member of the larger caspase family. Caspases are normally considered as either apoptotic or inflammatory, however in recent years many interactions across classes have been demonstrated. Here we examine how IECs are defended by caspase-1, but also that other normally apoptotic caspases are also involved in exfoliation. We will study the innate immune inflammasome sensors that drive exfoliation during bacterial infection, and also how different innate immune cells coordinate their activities to promote IEC exfoliation.

摘要 许多细菌病原体试图黏附或入侵肠上皮细胞(IECs)，通常使用 在IEC中操纵胞质信号通路的毒力因子。然而，IECS能够调查 通过使用炎症体家族中的先天免疫感受器来检测它们的胞浆。我们已经证明了 炎性小体可以通过检测细菌分泌系统的异常易位来检测细菌分泌系统的活性。 细菌鞭毛蛋白、杆状蛋白和针状蛋白。 炎症小体主要是在巨噬细胞中被研究的，其中活性caspase-1首次被显示为 保留前IL-1β和前IL-18至其成熟和释放的形式。Caspase-1最近被发现能够切割一种 第三种蛋白质，Gasdermin D，它在质膜上形成一个孔，导致程序性溶解细胞 死亡或上睑下垂。现在开始研究caspase-1在其他细胞类型中的功能，这些 可能与其在巨噬细胞中的功能略有不同。在这方面，在IECS中，炎性小体是最近 显示可促使受损的IEC脱落，并将其排入肠腔。 Caspase-1是较大的caspase家族的创始成员。Caspase通常被认为是 无论是凋亡性的还是炎症性的，然而，近年来许多跨类的相互作用 演示了。在这里，我们研究了Caspase-1如何保护IECs，以及其他正常凋亡细胞 半胱氨酸天冬氨酸酶也参与角质层剥离。我们将研究先天免疫炎症体感受器 细菌感染过程中的脱落，以及不同的天然免疫细胞如何协调它们的活动 促进IEC去角质。